Our objective was to evaluate the diagnostic utility of 2 new proliferation markers, cyclin D1 and minichromosome maintenance complex component 2 (MCM2), in comparison with p16, p53, and Ki67 in differentiating the spectrum of smooth muscle tumors. An institutional database search from 2009 to 2017 identified 10 cases of uterine leiomyoma with bizarre nuclei (LBN), 12 smooth muscle tumors of uncertain malignant potential, and 13 leiomyosarcomas (LMS). Ten resected leiomyomas (LM) were included as controls. Immunohistochemistry was performed on the befitting representative block from each case. Ki67 was <10% in all LMs and LBNs, whereas >10% in all LMSs. Although wild-type in majority of cases, p53 was overexpressed in 38% of LMSs. Cyclin D1 nuclear positivity in LMs, LBNs, and smooth muscle tumors of uncertain malignant potentials ranged from 0% to 65% of neoplastic cells with mostly weak to moderate staining intensity. Instead, cyclin D1 expression was <5% in all LMSs. The ratio of MCM2 positivity exhibited a similar wide range (<1%–80%) in LMs, LBNs, and smooth muscle tumors of uncertain malignant potentials but interestingly, 92% (12/13) of LMSs were diffusely and strongly positive for MCM2 (>80% cell positivity). Overall, for diagnosis of LMS, the sensitivity for diffuse intense MCM2 staining was higher (92%) compared with diffuse staining for p16 (77%); however, specificity of MCM2 and p16 was comparable (94% and 97%, respectively). Herein, we describe the immunohistochemical profile of 2 new proliferation markers, cyclin D1 and MCM2 in uterine smooth muscle tumors. A combination of diffuse strong MCM2 and p16 reactivity with increased Ki67 index can reliably distinguish LMSs from benign histologic mimics.